Developmental origins of mechanical homeostasis in the aorta

Abstract

Background: Mechanical homeostasis promotes proper aortic structure and function. Pathological conditions may arise, in part, from compromised or lost homeostasis. There is thus a need to quantify the homeostatic state and when it emerges. Here we quantify changes in mechanical loading, geometry, structure, and function of the murine aorta from the late prenatal period into maturity.Results: Our data suggest that a homeostatic set-point is established by postnatal day P2 for the flow-induced shear stress experienced by endothelial cells; this value deviates from its set-point from P10 to P21 due to asynchronous changes in mechanical loading (flow, pressure) and geometry (radius, wall thickness), but is restored thereafter consistent with homeostasis. Smooth muscle contractility also decreases during this period of heightened matrix deposition but is also restored in maturity. The pressure-induced mechanical stress experienced by intramural cells initially remains low despite increasing blood pressure, and then increases while extracellular matrix accumulates. Conclusions: These findings suggest that cell-level mechanical homeostasis emerges soon after birth to allow mechanosensitive cells to guide aortic development, with deposition of matrix after P2 increasingly stress shielding intramural cells. The associated tissue-level set-points that emerge for intramural stress can be used to assess and model the aorta that matures biomechanically by P56.

Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge

“…Notably, total elastic fiber area inferred via Movat staining, which is dominated by the elastic lamellae, was not reduced in any of the four BAPN-exposed Groups; indeed, it increased slightly when BAPN was started at 4 weeks of age. Although not visible in typical Movat-stained sections, intra-lamellar elastic fibers and fibrillin-1 microfibrils increase progressively in the normal rat aorta from 2+ weeks of age to maturity 38 , which may reflect the emerging need to mechano-sense the increasing wall stress 30 , with mechano-sensing critical to establishing a mechanically homeostatic aortic wall 40,41 . It is also thought that these intra-lamellar elastic fibers / microfibrils may improve the mechanical function or integrity of the lamellae within the media, interacting with other medial matrix components to protect against delamination 15,16 , and to connect the lamellae to the smooth muscle cells to facilitate phenotypic modulation [42][43][44] .…”

“…We initiated BAPN treatment at 4 weeks of age, which is after normal biomechanical maturation of the load-carrying elastic lamellae in WT mice but prior to maturation of intra-lamellar elastic fibers and mural collagen fibers 30,38,39 , to focus first on these possible contributors to wall integrity. Notably, total elastic fiber area inferred via Movat staining, which is dominated by the elastic lamellae, was not reduced in any of the four BAPN-exposed Groups; indeed, it increased slightly when BAPN was started at 4 weeks of age.…”

“…In this paper, we quantify consequences of LOX inhibition in the Fbn1 C1041G/+ mouse model of MFS using both standard and novel multi-modality biaxial quantification of mechanical properties with associated intramural imaging. To begin to delineate contributions of elastic fibers and fibrillar collagens to early disease progression, we contrast outcomes in female and male mice when LOX inhibition is initiated at 4 weeks of age, after elastic lamellar structures but not intra-lamellar elastic or collagen fibers have matured, and at 8 weeks of age, after the aorta has matured biomechanically 30 .…”

Progressive Microstructural Deterioration Dictates Evolving Biomechanical Dysfunction in the Marfan Aorta

“…Inasmuch as drug efficacy can depend on the age at initiation, as, for example, post-natal day P16 vs. P45 in mgR mice ( 36 ), there is a pressing need to quantify changes in microstructure and mechanics in these Marfan models as a function of maturation, noting that the aorta matures biomechanically by about P56 ( 37 ), which is one reason for our choice of P60. Most prior studies that included aging compared results in increasingly older (e.g., 3, 6, 9, and 12 months old) adult mice [e.g., ( 15 , 16 )], not developing mice.…”

Role of fibulin-5 insufficiency and prolapse progression on murine vaginal biomechanical function

“…Pearson’s or nonparametric Spearman’s correlations evaluated the relationship between contractility and passive mechanical properties with respect to prolapse grade. Motivated by prior work within other tissues demonstrating that contractility correlated with the passive mechanical properties, Pearson’s and nonparametric Spearman’s test evaluated the correlation between passive mechanical properties and contractility 65 . Motivated by prior work suggesting that elastic fibers may contribute to SMC contractility 15 – 18 , Pearson’s or Spearman’s test evaluated the correlation between contractility and elastin area fraction.…”